Somatostatins are neuropeptides originally discovered to inhibit growth hormone secretion by the pituitary. The actions of somatostatins are mediated by five related G protein receptor (GPCR) subtypes named sst1-5. In general, this signaling results in inhibition of hormone secretion and neuronal activity. Since their discovery, many roles of somatostatin have been described with specific effects dependent upon the receptor subtype involved and the cell type in which it is expressed. For example, somatostatin activity inhibits nociceptive signaling pathways via sst2 and sst4 receptor subtypes that are expressed at multiple sites: including peripheral nerve terminals, DRG neurons, the dorsal horn of the spinal cord, and spinal interneurons. Although clinical data is limited, two studies indicat the peripheral administration of the peptide sst2 agonist octreotide reduces pain intensity in patients with advanced gastrointestinal cancer and reduces the need for opioids in abdominal surgery patients. Both selective sst2 and sst4 agonists are effective in traditional rodent pain models. Chronic pain remains an important area of high unmet medical need that imposes an enormous burden on patients and their caregivers. In the US, Europe, and many other countries the prevalence of chronic pain is as high as one-fifth the population, with the prevalence of neuropathic pain estimated at 7-10%. Neuropathic pain conditions such as post-herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN) in particular are poorly relieved by current treatments such as anti-epileptics and anti-depressants due to a lack of efficacy and/or dose-limiting side effects. As part of our SBIR-funded effort to discover sst2 agonists for the treatment of pituitary GH-secreting adenomas that cause acromegaly, we have also discovered potent, drug-like small molecule sst4 agonists as well as sst4/2 dual-agonists. In the Phase I portion of this Fast Track application, three of these compounds (all potent sst4 agonists with differing levels of sst2 activity) will be profiled in acute efficacy studies in innovative rat modls that better mimic PDN and PHN to provide a target receptor specificity profile. This will be used to guide medicinal chemistry efforts to identify additional Leads in Phase II, with the best compounds advancing to testing models of chronic pain models and initial toxicology studies to select an IND Development Candidate based on the preliminary therapeutic window for each. If successful, this project will result in the selection of a drug candidate for pre-IND enabling toxicology studies to support first-in-human studies. Ultimately, this molecule would be evaluated in later stage clinical trials as a potential First-In-Class treatment for post-herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN), with the potential to be evaluated in other forms of neuropathic pain.